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Abstract:

An inhalable pharmaceutical solution aerosol comprising beclometasone
dipropionate, ethanol and a propellant selected from
1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and a mixture
thereof, wherein the aerosol has a droplet size having a mass median
aerodynamic diameter of 0.5-2.0 μm, for maintaining lung function
above 60% of baseline FEV1, or reducing the occurrences of lung
function falling below 60% of baseline FEV1.

Claims:

1. An inhalable pharmaceutical solution aerosol comprising beclometasone
dipropionate, ethanol and a propellant selected from
1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and a mixture
thereof, wherein the aerosol has a droplet size having a mass median
aerodynamic diameter of 0.5-2.0 μm, for maintaining lung function
above 60% of baseline FEV1, or reducing the occurrences of lung
function falling below 60% of baseline FEV .sub.1.

2. An inhalable pharmaceutical solution aerosol as claimed in claim 1,
comprising 0.02 to 0.6 percent by weight beclometasone dipropionate, 1 to
20 percent by weight ethanol and 80 to 99 percent by weight of
propellant, wherein the percentages by weight are based on the total
weight of the solution aerosol.

3. An inhalable pharmaceutical solution aerosol as claimed in claim 1,
consisting essentially of beclometasone dipropionate, ethanol and a
propellant selected from 1,1,1,2-tetrafluoroethane,
1,1,1,2,3,3,3-heptafluoropropane and a mixture thereof.

4. An inhalable pharmaceutical solution aerosol as claimed in claim 1,
wherein the aerosol has a droplet size having a mass median aerodynamic
diameter of 0.8-1.2 μm.

7. A method for maintaining lung function above 60% of baseline
FEV1, or reducing the occurrences of lung function falling below 60%
of baseline FEV1 by administering to a patient in need thereof, an
inhalable pharmaceutical solution aerosol comprising beclometasone
dipropionate, ethanol and a propellant selected from
1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and a mixture
thereof, wherein the aerosol has a droplet size having a mass median
aerodynamic diameter of 0.5-2.0 μm.

Description:

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application is related to and claims the benefit of U.S.
Provisional Application No. 61/304,998, filed on Feb. 16, 2010, the
contents of which are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

[0002] This invention relates to an inhalable pharmaceutical composition,
and particularly to an inhalable pharmaceutical solution aerosol
comprising beclometasone dipropionate.

BACKGROUND OF THE INVENTION

[0003] Asthma is a common inflammatory disease in which the airways of the
respiratory system become chronically narrowed and constricted by oedema
(fluid retention). During an attack, a patient suffers from laboured
breathing accompanied especially by wheezing and coughing and by a sense
of constriction in the chest due to bronchospasm (sudden constriction of
the muscles in the walls of the bronchioles), mucosal oedema and mucus
formation. Asthma is triggered by hyperreactivity to various stimuli
(such as allergens or a rapid change in air temperature). In sensitised
individuals, inhaled allergens (allergy triggers) provoke a hyperimmune
response characterised by recruitment of immune cells and production of
immunoglobulin E (IgE) antibodies. Asthma is caused by the attachment of
IgE antibodies to mast cells (a resident cell of several types of tissues
throughout the body, particularly in proximity to surfaces that interface
the external environment). This attachment activates mast cells and on
renewed exposure to the same antigen, degranulation of the mast cells
occurs, leading to the rapid release of inflammatory mediators, such as
histamine, proteoglycans, and cytokines. Asthma is a result of localised
release of such mediators.

[0004] In a patient suffering from asthma, airflow obstruction is largely
reversible and the patient experiences a significant response to inhaled
bronchodilators and inhaled antiinflammatories.

[0005] Asthma is generally treated using a combination of long-term
treatment and short-term episodic treatment of acute attacks. Long-term
treatment of asthma involves the use of antiinflammatories and
long-acting bronchodilators. Short-term episodic treatment employs
short-acting bronchodilators. Inhaled glucocorticosteroids (ICS) are a
feature of the currently preferred treatment for moderate to severe
allergic asthma, and have been shown to act by suppressing the adaptive
immune response while not suppressing innate immune response. There are
various effective ICSs available in the art, for example, fluticasone
propionate or CFC-beclometasone (a formulation comprising beclometasone
dipropionate and a chlorofluorocarbon propellant).

[0006] Beclometasone dipropionate (INN), also known as beclomethasone
dipropionate (USAN) or
(8S,9R,10S,11S,13S,14S,16S,17R)-9-chloro-11-hydroxy-10,13,16-trimethyl-3--
oxo-17-[2-(propionyloxy)acetyl]-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydr-
o-3H-cyclopenta[a]phenanthren-17-yl propionate (IUPAC), is the subject of
the present invention.

[0007] Formulations of beclometasone dipropionate are known in the art.
For example, U.S. Pat. No. 5,776,432 discloses a pharmaceutical solution
aerosol formulation comprising beclometasone dipropionate, a
hydrofluorocarbon propellant selected from 1,1,1,2-tetrafluoroethane
(norflurane or propellant 134a), 1,1,1,2,3,3,3-heptafluoropropane
(propellant 227) and a mixture thereof, and ethanol (anhydrous) to
solubilise the beclometasone dipropionate in the propellant. The
beclometasone dipropionate is dissolved in the formulation, and the
formulation is substantially free of surfactant.

[0008] However, further improvements in treatment are desired for the
effective management of asthma.

[0010] This formulation provides a surprising improvement in the lung
(pulmonary) function compared to other known ICSs.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 shows in schematic form the study design used in the trials
described in the Example.

[0012]FIG. 2 shows the adjusted odds ratio for successful asthma control
observed for various corticosteroids in the trials described in the
Example.

[0013]FIG. 3 shows the adjusted odds ratio (revised definition) for
successful asthma control observed for various corticosteroids in the
trials described in the Example.

[0014]FIG. 4 shows the adjusted rate ratio for exacerbation rate observed
for various corticosteroids in the trials described in the Example.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The inhalable pharmaceutical solution aerosol of the present
invention comprises beclometasone dipropionate, ethanol and a propellant
selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane
and a mixture thereof.

[0016] The active ingredient beclometasone dipropionate is generally
present in a formulation of the invention in a therapeutically effective
amount, i.e. an amount such that metered volumes of the medicament
administered to the patient contains an amount of drug effective to exert
the intended therapeutic action. The aerosol solution preferably contains
0.02 to 0.6 percent by weight, more preferably 0.05 to 0.5 percent by
weight of beclometasone dipropionate, based on the total weight of the
solution.

[0017] Ethanol is present in an amount effective to solubilise the
beclometasone dipropionate in the propellant. Preferably, the solution
contains 1 to 20 percent by weight of ethanol, more preferably 2 to 12
percent by weight and most preferably 4 to 10 percent by weight, based on
the total weight of the aerosol solution. The ethanol will be present in
an amount sufficient to dissolve substantially all of the medicament
present in the formulation and to maintain the medicament dissolved over
the time period and conditions experienced by commercial aerosol
products. Preferably the ethanol is present in an amount to prevent
precipitation of the active ingredient even at temperatures down to
-20° C. The ethanol is preferably anhydrous ethanol, although
trace amounts of water absorbed by the ingredients, for example during
manufacture of the medicament, may be tolerated.

[0018] The hydrofluorocarbon propellant may be propellant 134a, propellant
227 or a mixture thereof. The solution preferably contains 80 to 99
percent by weight of propellant, more preferably 88 to 98 percent by
weight, and most preferably 90 to 95 percent by weight, based on the
total weight of the aerosol solution. The hydrofluorocarbon propellant is
preferably the only propellant present in the formulations of the
invention.

[0019] The solution of the present invention is preferably substantially
free of surfactant. Surfactants are often added to suspensions to
stabilise the suspension. However, since the formulation of the present
invention is a solution, a surfactant is not required. Nevertheless,
small quantities can be tolerated without adversely affecting the
formulation. Preferably the formulation contains no more than 0.0005
percent by weight of a surfactant based on the total weight of the
solution. Preferred formulations contain no surfactant. Presence of a
significant amount of a surfactant is believed to be undesirable for
solution formulations of beclometasone dipropionate because surfactants
such as oleic acid and lecithin are believed to promote chemical
degradation of the active ingredient when the latter is dissolved in the
mixture of the propellant and ethanol.

[0020] A preferred solution according to the present invention comprises
0.02 to 0.6 percent by weight beclometasone dipropionate, 1 to 20 percent
by weight ethanol and 80 to 99 percent by weight of propellant, wherein
the percentages by weight are based on the total weight of the solution
aerosol. A particularly preferred solution consists essentially of
beclometasone dipropionate, ethanol and a propellant selected from
1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and a mixture
thereof; more preferably the solution consists of these components.

[0021] The solution of the present invention may be prepared by dissolving
the desired amount of beclometasone dipropionate in the desired amount of
ethanol accompanied by stirring or sonication. An aerosol container may
then be filled using conventional cold-fill or pressure-fill methods.

[0022] The solution aerosol of the present invention is administered from
a pressurised metered-dose inhaler (pMDI). A pMDI has two key components,
namely a canister and an actuator (or mouthpiece). The canister has a
vial for storing the solution coupled to a metering dose valve having an
actuating stem. The container is housed in an actuator where the
actuating step is in fluid communication with a discharge nozzle in the
actuator. Actuation of the device releases a single metered dose of
solution aerosol. The aerosol passes through the discharge nozzle
resulting in a breaking up of the volatile propellant into droplets,
followed by rapid evaporation of these droplets as they are inhaled into
the lungs. The discharge nozzle preferably has an orifice diameter of
100-300 μm, more preferably 150-250 μm and most preferably 248
μm. This orifice size encourages the formation of droplets of the
required size in the aerosol solution of the present invention.

[0023] The solution of the present invention when administered from the
pMDI forms a fine aerosol of droplets which has a droplet size having a
mass median aerodynamic diameter of 0.5-2.0 μm and preferably 0.8-1.2
μm. This small droplet size facilitates deep lung penetration. The
droplet size may be measured using conventional techniques, such as using
a Next Generation Pharmaceutical Impactor (NGI) or an Andersen
eight-stage impactor (ACI).

[0024] It has been found that the solution aerosol of the present
invention is capable of providing improved lung function and is able to
maintain lung function above 60% of baseline FEV1, or to reduce the
occurrences of lung function falling below 60% of baseline FEV1 in a
patient suffering from asthma. Preferably the solution aerosol of the
present invention may be used for maintaining lung function above 70% of
baseline FEV1, or reducing the occurrences of lung function falling
below 70% of baseline FEV1, and more preferably for maintaining lung
function above 80% of baseline FEV1, or reducing the occurrences of
lung function falling below 80% of baseline FEV1. Reducing the
occurrences is compared to a patient taking no ICS or even other ICS,
such as fluticasone propionate and/or CFC-beclometasone dipropionate.

[0025] FEV1 is the maximal volume of air exhaled in the first second
of a forced expiration from a position of full inspiration, expressed in
litres at body temperature and ambient pressure saturated with water
vapour (BTPS). FEV1 is determined by spirometry which is the most
common of the Pulmonary Function Tests (PFTs). FEV1 is measured
according to the parameters set down in the joint statements on lung
function testing by the American Thoracic Society (ATS) and the European
Respiratory Society (ERS), see the Series "ATS/ERS Task Force:
Standardisation of Lung Function Testing, Edited by V. Brusasco, R. Crapo
and G. Viegi, Numbers 1-5, Eur. Respir. J. 2005; 26:
153-161,319-338,511-522,720-735 and 948-968.

[0026] The FEV1 obtained is expressed in litres for an individual
patient. It must then be compared to a reference (predicted) value based
on healthy subjects. Predicted values are obtained from studies of
normal, healthy subjects with the same anthropometric (sex, age and
height) and ethnic characteristics of the patient being tested. Reference
values are derived from large groups of volunteers. The criteria to
define subjects as normal or healthy have been laid down the ATS and ERS.

[0027] The result is an FEV1 expressed as a percentage of predicted.
The severity of the asthma is defined by this percentage. The ATS/ERS
statements lay down the following definitions: mild asthma is an
FEV1 of 70% of predicted or above; moderate 60-69% of predicted;
moderately severe 50-59% of predicted; severe 35-49% of predicted and
very severe less than 35% of predicted The percentage provides a baseline
measurement for any given patient. It has been found that the solution
aerosol of the present invention maintains the baseline for a given
patient within the above-described limits.

[0028] A group of patients has also been identified which receive
particular benefit from the solution aerosol of the present invention.
That is, a patient showing insufficient response to inhalable fluticasone
propionate and/or an inhalable formulation comprising beclometasone
dipropionate and a chlorofluorocarbon propellant. An insufficient
response herein is defined as failing to maintain the baseline for a
given patient within the above-described limits.

[0029] The present invention also provides a method for maintaining lung
function above 60% of baseline FEV1, or reducing the occurrences of
lung function falling below 60% of baseline FEV1 by administering to
a patient in need thereof, an inhalable pharmaceutical solution aerosol
comprising beclometasone dipropionate, ethanol and a propellant selected
from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane and a
mixture thereof, wherein the aerosol has a droplet size having a mass
median aerodynamic diameter of 0.5-2.0 μm.

[0030] The present invention will now be described with reference to the
following example, which is not intended to be limiting.

EXAMPLE

[0031] Trials were conducted using Qvar® which is a solution aerosol
formulation containing beclometasone dipropionate, anhydrous ethanol, and
propellant 134a (1,1,1,2-tetrafluoroethane). Qvar® is available in
two doses, 50 μg and 100 μs. The two formulations contain:
beclometasone dipropionate 0.05 or 0.10 mg per actuation, anhydrous
ethanol 4.74 mg per actuation and propellant 134a 54.51 or 54.46 mg per
actuation. Both formulations have a density at 20° C. of 1.166
g/mL and a MMAD of 1.1 μm.

[0032] Qvar® and other inhaled corticosteroids (ICS) CFC-beclometasone
(BDP) and fluticasone propionate (FP) were compared in a large
representative, UK clinical database.

[0033] Asthma patients, aged 5-60, without other chronic respiratory
diseases, receiving Qvar®, CFC-BDP or FP MDIs (Multiple Dose
Inhalers) who subsequently had an ICS increase between January 1997-June
2006 were identified from UK General Practice Research Database. Patients
were eligible if they had data available for the twelve months prior to
AND twelve months after the date of ICS increase. Multiple logistic
regression, adjusted for baseline severity, provided odds of successful
asthma control (no asthma hospital attendances, oral steroids,
consultations or hospital admissions for lower respiratory tract
infections requiring antibiotics) during 12 month follow-up. Poisson
regression was used to compare asthma exacerbation rates (unscheduled
hospital admissions/A&E attendances for asthma or use of oral steroids).

[0035] Patients receiving increased ICS therapy with Qvar® were more
likely to achieve successful asthma control and less likely to experience
exacerbations.

[0036] Study Design: A retrospective, observational, cohort study design
was used, consisting of two time periods: a baseline period for
confounder definition (minimum of one year before index prescription
date) and an outcome period of one year post-index prescription date. The
study design is shown in schematic format in FIG. 1.

[0037] Statistical Analysis: Descriptive statistics were used to compare
baseline outcomes. Multiple logistic regression, adjusted for baseline
severity and other potential confounders found at baseline, was used to
determine the odds of successful asthma control. Poisson regression was
used to compare exacerbation rates.

[0039] Secondary Primary Outcome: Proxy for successful asthma control
defined as above with the additional criteria of average daily prescribed
dose of salbutamol of no more than 200 mcg and terbutaline 500 mcg
(SABA).